You are on page 1of 11

REVIEW

European Heart Journal (2014) 35, 147155


doi:10.1093/eurheartj/eht409

ESC 2013 Andreas Gruntzig Lecture

Reperfusion therapy of acute ischaemic stroke


and acute myocardial infarction: similarities
and differences
Petr Widimsky 1*, Rita Coram 2, and Alex Abou-Chebl 3
1
Cardiocenter, Third Faculty of Medicine, Charles University Prague, Ruska 87, 100 00 Prague 10, Czech Republic; 2Department of Cardiology, University of Louisville, Louisville, KY, USA;
and 3Department of Neurology, University of Louisville, Louisville, KY, USA

The evolution of reperfusion therapy in acute myocardial infarction and acute ischaemic stroke has many similarities: thrombolysis is superior to
placebo, intra-arterial thrombolysis is not superior to intravenous (i.v.), facilitated intervention is of questionable value, and direct mechanical
recanalization without thrombolysis is proven (myocardial infarction) or promising (stroke) to be superior to thrombolysisbut only when
started with no or minimal delay. However, there are also substantial differences. Direct catheter-based thrombectomy in acute ischaemic
stroke is more difficult than primary angioplasty (in ST-elevation myocardial infarction [STEMI]) in many ways: complex pre-intervention diagnostic workup, shorter time window for clinically effective reperfusion, need for an emergent multidisciplinary approach from the first
medical contact, vessel tortuosity, vessel fragility, no evidence available about dosage and combination of peri-procedural antithrombotic
drugs, risk of intracranial bleeding, unclear respective roles of thrombolysis and mechanical intervention, lower number of suitable patients,
and thus longer learning curves of the staff. Thus, starting acute stroke interventional programme requires a lot of learning, discipline, and humility.
Randomized trials comparing different reperfusion strategies provided similar results in acute ischaemic stroke as in STEMI. Thus, it might be
expected that also a future randomized trial comparing direct (primary) catheter-based thrombectomy vs. i.v. thrombolysis could show superiority of the mechanical intervention if it would be initiated without delay. Such randomized trial is needed to define the role of mechanical intervention alone in acute stroke treatment.

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Myocardial infarction Acute stroke Reperfusion Thrombolysis Primary angioplasty Catheter


intervention Thrombectomy

Introduction
Acute regional ischaemia with progressive necrosis developing
quickly during the initial hours after arterial thrombotic occlusion is
a common feature of acute myocardial infarction and acute ischaemic
stroke. Both these diseases are leading causes of death worldwide.
Restoration of antegrade blood flow in the acutely occluded artery
(i.e. reperfusion of the ischaemic tissue) is the most effective
therapy in both situations (Figures 1 and 2). Timely reperfusion
halts the progress of necrosis and preserves viable tissue (myocardium in jeopardy or cerebral penumbra).

The pathophysiology of cerebral infarction is different from myocardial infarction. Whereas in myocardial infarction thrombotic arterial occlusion over the ruptured coronary plaque can be found in
90 95% of patients, acute stroke in many patients cannot be
simply attributed to a cerebral vessel occlusion (e.g. lacunar cerebral
infarction has completely different aetiology). The differences
between these two diseases are at least as important as the similarities, and the treatment should be done by physicians having these differences in mind (Table 1).
Reperfusion therapy of acute myocardial infarction using
thrombolytic agents was first used by Chazov et al.1 in 1976 and

* Corresponding author. Tel: +420 267163159, Fax: +420 267162621, Email: petr.widimsky@fnkv.cz
& The Author 2013. Published by Oxford University Press on behalf of the European Society of Cardiology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which
permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
journals.permissions@oup.com

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 15, 2014

Received 29 May 2013; revised 18 August 2013; accepted 13 September 2013; online publish-ahead-of-print 3 October 2013

148

P. Widimsky et al.

infarction [STEMI] (two acutely occluded coronary arteries). (A) Thrombotic occlusion of the proximal right coronary artery on admission. (B)
Widely patent (near-normal) right coronary artery after stent implantation. (C) Thrombotic occlusion of the proximal obtuse marginal branch
on admission. (D) Widely patent (near-normal) obtuse marginal branch after stent implantation.

Figure 2 Carotid angiography before and after catheter-based thrombectomy in acute anterior circulation stroke. (A) Thrombotic occlusion of
the middle cerebral artery on admission. (B) Widely patent (near-normal) middle cerebral artery after catheter-based thrombectomy.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 15, 2014

Figure 1 Coronary angiography before and after primary percutaneous coronary intervention in a patient with double ST-elevation myocardial

149

Reperfusion therapy of acute stroke

Table 1

Similarities and differences between acute myocardial infarction and acute stroke
Acute myocardial infarction

Acute ischaemic stroke

Pathophysiology

Arterial occlusion + ischaemic necrosis in nearly


all cases

Arterial occlusion + ischaemic necrosis in only


half of the cases

Clinical picture
Prognosis

Acute onset
High mortality (if untreated by reperfusion)

Acute onset
High mortality and permanent disability

Effective treatment

Reperfusion therapy

Reperfusion therapy

Aetiology

Uniform: plaque rupture + thrombosis in situ in


9095%

Multifactorial: cardioembolic, arterioembolic,


thrombosis in situ, lacunar, cryptogenic

Arterial occlusive thrombus feasible for


catheter-based intervention

Found in 9095% of acute coronary angiograms

Found only in 4050% of acute


CT-angiograms

Time window symptom onsetintervention start


(to offer benefit and not harm)

24 h (48 h in some patients)

3 h (8 h in some patients)

Reperfusion damage

Only theoretically, clinically is reperfusion


beneficial

Reperfusion damage (parenchymal bleeding) is


a real clinical problem

Clinical picture

Pain (dyspnoea) alerts most patients to call early


for help

Neurological dysfunction and absence of pain


frequently results in late medical contact

Diagnostic method before reperfusion therapy


indication

ECG (fast, simple, cheap, at the site of first


medical contact)

CT (takes more time, expensive, in-hospital)

Laboratory diagnostic marker

Troponin (although not needed for the initial


decision in ST-elevation myocardial
infarction)

Not yet available

Contraindications for catheter-based intervention

None

Intracranial bleeding or advanced ischaemia on


CT

Percentage of hospitalized patients who undergo


reperfusion therapy in well-functioning health
care systems

.90%

,10%

...............................................................................................................................................................................
Similarities

...............................................................................................................................................................................
Differences

There is a marked difference in the use of reperfusion therapy for


acute myocardial infarction and for acute ischaemic stroke. In the
USA during 2009, only 4.5% of ischaemic strokes were treated by i.v.
thrombolysis.16 The situation is similar in Europe. In the Czech Republic, 4% of all hospitalized strokes are treated by thrombolysis and 0.3%
by the combination of thrombolysis with mechanical intervention. On
the other hand, nearly all STEMI patients are treated by primary percutaneous coronary intervention (PCI) in many European countries
e.g. the Czech Republic, The Netherlands, Sweden, Germany,
Poland, and many others as was shown by the Stent for Life initiative.17
This initiative helped to improve STEMI treatment in many European
countries during the last few years.18 In other countries (e.g. UK, Slovakia, and others) similar improvement was achieved by the joint initiative of cardiologists and local governments.
Although cardiologists succeeded to decrease the in-hospital case
fatality of unselected acute myocardial infarction to current 5 8%
during the last 20 years, case fatality of acute stroke in many countries
remained almost unchanged. In the USA, the population mortality of
stroke decreased (from #3 cause of death to #4 cause of death), and
much of this improvement is attributed to care in primary stroke
centres and in specialized stroke units. Thrombolysis has not been
associated with reductions in case fatality due to acute ischaemic
stroke. Many cardiologists worldwide (after having fully developed
STEMI networks in their regions) are increasingly interested in

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 15, 2014

was introduced into broad clinical practice 10 years later after the
publication of the pivotal randomized clinical trials GISSI2 and
ISIS-2.3 Mechanical recanalization by means of primary angioplasty
was first used by Meyer et al.4 and Hartzler et al.5 The first three randomized clinical trials showing superiority of primary PTCA over
thrombolysis in ST-elevation myocardial infarction [STEMI] were
published by Zijlstra et al.,6 Grines et al.,7 and Gibbons et al.8 in
1993. It took another 9 years before the Czech Society of Cardiology
published the worlds first official guidelines recommending primary
angioplasty as the first-choice therapy for STEMI.9
The history of reperfusion therapy in acute ischaemic stroke is
even more complicated. The first attempts to treat acute stroke by
thrombolysis were reported in 1976.10 The first small randomized
trial showing potential benefits of thrombolysis when used early in
acute stroke was published in 1992,11 and in 1995 the first positive
randomized trial of thrombolysis was published.12 The first official
guidelines recommending thrombolysis for acute stroke were published in 2003.13 Direct mechanical reperfusion using catheter-based
thrombectomy without thrombolysis was first used in 2001,14 and
there is yet no randomized trial completed to date comparing
mechanical reperfusion (without thrombolysis) vs. intravenous
(i.v.) thrombolysis. Thus, the latest official guidelines15 do not yet
recognize direct mechanical intervention as the accepted routine
therapy for acute stroke.

150

Intravenous thrombolysis vs.


conservative treatment
Many randomized clinical trials confirmed superiority of i.v. thrombolysis over placebo in STEMI when used early after symptom onset
(Figure 3). The rate of intracranial bleeding was 0.5 1.4% in a
meta-analysis.19
In acute stroke, one of the two most positive thrombolytic trials12
did not show significant mortality benefit (17.3% 3-month mortality
after thrombolysis vs. 20.5% mortality after placebo, P 0.30), but
found a significant decrease in overall unfavourable outcome
(death or severe disability defined as modified Rankin Scale
(mRS) . 2 was found in 57% after thrombolysis vs. 73% after
placebo)the difference caused by 13% absolute reduction in permanent disability. Symptomatic intracranial (6.4% thrombolysis vs.
0.6% placebo) as well as overall fatal (2.9% thrombolysis vs. 0.3%
placebo) bleeding was significantly higher after recombinant tissue
plasminogen activator (rt-PA).
The ECASS-III trial20 enrolled 821 patients treated between 3 and
4.5 h after the onset of a stroke. Fewer patients had an unfavourable

Figure 3 Comparison of intravenous thrombolysis vs. placebo in acute myocardial infarction and acute stroke. (A) Hard clinical endpoints, i.e.
death/re-infarction/stroke for STEMI patients and death/severe disability (modified Rankin Scale [mRS] . 2) for stroke patients. (B) All-cause mortality. (C) Symptomatic intracranial haemorrhage. Adopted from references 3,12, and 22.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 15, 2014

acute stroke treatment. The interventional treatment of acute stroke


(unlike acute myocardial infarction) requires effective cooperation
between several medical specialities. The leading neurologists, neurosurgeons, and neuroradiologists recognize the possibilities of effective regional STEMI networks (enabling 24/7 service for acute
interventions) and are opening their minds to future cooperation
with cardiologists to improve the patient access to this modern
therapy. However, there remain many obstacles, including resistance
of neurosciences specialists to the concept of non-neurosciencestrained physicians caring for and performing interventions on patients
with stroke. These attitudes are due to typical issues such as turf
battles, financial concerns, as well as the relatively small number of
patients who may be eligible for treatment, but also important and
relevant concerns regarding knowledge of cerebral physiology,
anatomy, and stroke management.
Of course, this review article reflects the point of view of the
authorstwo cardiologists and one neurologist. The authors recognize that others might have somewhat different views. The aim of this
contribution is not to give recommendations, but rather to stimulate
interdisciplinary discussion.

P. Widimsky et al.

151

Reperfusion therapy of acute stroke

route (40 45%) did not result in improved clinical outcomes.


Thus, the intracoronary administration of thrombolytic agents was
completely abandoned .20 years ago.
Meta-analysis of 15 studies29 on combined i.v. + intra-arterial (i.a.)
thrombolytic therapy in acute stroke found 35.1% complete recanalization rate, 17.9% mortality, 51.1% unfavourable outcome (death or
disability mRs . 2 at 90 days), and 8.6% sICH (proven haemorrhage
with an increase of National Institute of Health Stroke Scale (NIHSS)
by 4 points). Neither mortality difference nor difference in sICH
was found when combined lytic therapy was compared with i.v.
thrombolysis alone.
The PROACT-II trial randomized 180 patients with angiographically proven middle cerebral artery occlusion treated within 6 h of
stroke onset to either i.a. thrombolysis or placebo. Mechanical manipulation of the thrombus was not permitted. The study showed
clinical superiority of thrombolysis (40% good neurological outcomesmRS 2) over placebo (25% mRS 2). The rate of sICH
was 10.9% with thrombolysis and 2% with placebo. There was no difference in 90-day mortality.30
The Japanese MELT trial used i.a. urokinase in patients with M1 or
M2 MCA occlusions of ,6 h duration.31 The trial was stopped after
enrolling 114 patients because of Japanese approval of IV tPA. The
primary endpoint (mRS 2) was not significantly different compared with placebo, and the rate of sICH was 9%. However, a preplanned secondary analysis showed that the rate of recovery to
normal or near normal (mRS 1) was higher in the treatment
group (42.1 vs. 22.8%, P 0.045).
The data from these two trials show the efficacy of IAT compared
with placebo in the treatment of patients with angiographically
proven MCA occlusion. Although there has been no direct, pure
comparison of IA thrombolysis vs. i.v. thrombolysis, it is known32 35
that recanalization rates for large-vessel occlusion are generally poor
with i.v. tPA (e.g. MCA recanalization rate is 33%, ICA recanalization is 8%, and patients with thrombi .8 mm do not recanalize
with i.v. tPA). Unfortunately, the initiation of IAT is much more timeconsuming than i.v. tPA; therefore, the potential benefit may be lost
due to the delay in treatment onset. Furthermore, the sICH rates
10%31,32 after i.a. thrombolysis are rather high.
Thus, there is no direct evidence (neither for acute myocardial infarction nor for acute stroke) that i.a. administration of a fibrinolytic
agent is of any superior clinical value over simple i.v. thrombolysis alone.

Intravenous plus/vs. intra-arterial


thrombolysis

Many randomized trials in STEMI36 39 and others tested the attractive hypothesis: to use i.v. thrombolysis at the time of first medical
contact (to save time), followed by coronary angiography and angioplasty (to maximize the recanalization rates) (Figures 5 and 6).
However, all these trials failed to show benefit of this approach
over direct angioplasty alone. The results of most trials almost
copied the two similarly designed three-arm trials28,36: facilitated
angioplasty was slightly superior to i.v. thrombolysis alone, but was
far less effective than primary angioplasty alone. The explanation is
complex, but most important are two differences favouring

Historically, thrombolysis was introduced to STEMI treatment as


intracoronary infusion (Figure 4).1,24 26 However, it was soon recognized that i.v. infusion of a fibrinolytic agent is able to achieve the
same clinical benefit with the same (or even lowerdue to lack of
arterial punctures and lack of mechanical manipulations in a hypocoagulable state) bleeding risk.27,28 The slightly higher recanalization
rates (5060%) achieved with intracoronary thrombolysis over i.v.

Facilitated intervention
(thrombolysis 1 mechanical
intervention)

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 15, 2014

outcome (death or severe disability) with alteplase over placebo (48


vs. 55%; P 0.04). The incidence of symptomatic intracranial haemorrhage (sICH) was higher with alteplase than with placebo (2.4 vs.
0.2%; P 0.008). Mortality did not differ significantly between the
alteplase and placebo groups (7.7 and 8.4%, respectively; P 0.68).
The Third International Stroke Trial (IST-321) randomized 3035
elderly (53% were .80 years) patients with acute ischaemic
stroke ,6 h from symptom onset in two groups: (i) i.v. rt-PA or
(ii) control treatment. Unfavourable outcome (death or disability
by Oxford Handicap Score .2) at 6 months was found in 63%
(rt-PA) vs. 65% (control, P 0.181). Fatal or non-fatal sICH within
7 days occurred in 7% after rt-PA vs. 1% in the control group. Early
mortality was 11% (rt-PA) vs. 7% (control group, P 0.001)
total 6-month mortality was equal in both groups (27%).
A comprehensive meta-analysis comparing i.v. thrombolysis vs.
conservative therapy for acute stroke22 included 26 trials involving
7152 patients. Thrombolytic therapy within 6 h from symptom
onset increased the risk of sICH (OR 3.49, 95% CI 2.814.33) and
death (OR 1.31, 95% CI 1.141.50) at 36 months post-stroke.
However, the proportion of patients who were dead or dependent
(modified Rankin 36) at 36 months after stroke was reduced
(odds ratio 0.81, 95% confidence interval 0.730.90). Treatment
within 3 h was more effective at reducing the combined endpoint
of death or dependency (OR 0.71, 95% CI 0.52 0.96) but had no
effect on mortality (OR 1.13, 95% CI 0.86 1.48).
Another meta-analysis23 included 3670 patients from eight trials
using rt-PA (ECASS-III, EPITHET, and six older trials) and was
focused on the time window between symptom onset and start of
thrombolysis. Favourable 3-month outcome (defined as modified
Rankin score 0 1) increased as time delay decreased (P 0.0269)
and there was no benefit of rt-PA treatment beyond 270 min.
Benefit was greater the earlier patients were treated: adjusted odds
of a favourable 3-month outcome were 2.55 (95% CI 1.44 4.52)
for 0 90 min, 1.64 (1.122.40) for 91 180 min, 1.34 (1.061.68)
for 181 270 min, and 1.22 (0.921.61) for 271 360 min. Large
ICH occurred in 5.2% of patients assigned to alteplase and 1.0% of
controls, with no relationship to time delays. However, mortality
increased with time delay [P 0.0444: adjusted odds were 0.78
(0.411.48) for 090 min, 1.13 (0.701.82) for 91180 min, 1.22
(0.871.71) for 181270 min, and 1.49 (1.002.21] for 271360 min.
Thus, i.v. thrombolysis is superior to placebo for both diseases
(acute myocardial infarction and acute stroke) provided it is used
timely: within ,12 h in STEMI (with maximum benefit within
,6 h) and within ,4.5 h in acute stroke (with mortality benefit
only within ,90 min).

152

P. Widimsky et al.

i.e. death/re-infarction/stroke for STEMI patients and death/severe disability (mRS . 2) for stroke patients. (B) All-cause mortality. (C) Symptomatic
intracranial haemorrhage. Adopted from references 24 26 and 29.

primary over facilitated PCI: higher rates of re-infarction (including


stent thrombosis) and higher rates of bleeding complications (including cardiac tamponade) after facilitated PCI.
The recently published STREAM trial randomized selected
patients (unable to undergo primary PCI within 1 h from the first
medical contact) to either pre-hospital fibrinolysis with subsequent
coronary angiography (+PCI) or primary PCI. The trial found
similar outcomes in both groups. However, fibrinolysis was associated with a slightly increased risk of intracranial bleeding.39
The Interventional Management of Stroke (IMS 3) trial40 compared i.v. thrombolysis (tPA) alone vs. facilitated intervention (i.v.
tPA + i.a. tPA or mechanical thrombectomy). The trial has suspended enrolment for futility. A major limitation of the IMS III trial
was that patients were selected upon clinical grounds and only 47%
had a CT angiogram (CTA). In a pre-planned analysis of the patients
with a documented arterial occlusion by CTA, there was a significant
benefit in favour of facilitated intervention (P 0.01).
These data on combined therapy demonstrate that there is no
benefit from facilitated intervention (i.v. thrombolysis followed by i.a.
thrombolysis + catheter intervention) over i.v. thrombolysis alone in
acute stroke patients when used as a primary strategy. However, in

patients with failed i.v. thrombolysis and in some selected patients


with a large thrombus burden, IAT can be considered for rescue
therapy. This is very similar to the situation in acute myocardial infarction 25 years ago (intracoronary thrombolysis was not superior to i.v.
thrombolysis) or more recently (facilitated PCI was not shown to be
superior in several trials).

Primary catheter-based
intervention (primary
percutaneous coronary
intervention, direct catheter-based
thrombectomy)
The benefits of primary PCI over thrombolysis in STEMI were clearly
demonstrated 20 years ago (Figure 7).6 8 These benefits are present
even when patients require transportation from the first medical
contact site to the nearest PCI-capable hospital.41,42 A large
meta-analysis has demonstrated this benefit unequivocally.43

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 15, 2014

Figure 4 Comparison of intra-arterial vs. intravenous thrombolysis in acute myocardial infarction and acute stroke. (A) Hard clinical endpoints,

Reperfusion therapy of acute stroke

153

Figure 6 Comparison of facilitated intervention vs. catheter


intervention alone in acute myocardial infarction and acute
stroke. Adopted from references 28 and 36 (STEMI); no randomized trials available for acute stroke.

Figure 7 Comparison of catheter intervention alone vs. intravenous thrombolysis alone in acute myocardial infarction and acute
stroke. Adopted from reference 43 (STEMI); no randomized trials
available for acute stroke.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 15, 2014

Figure 5 Comparison of intravenous thrombolysis vs. lysis-facilitated intervention in acute myocardial infarction and acute stroke. (A) Hard clinical endpoints, i.e. death/re-infarction/stroke for STEMI patients and death/severe disability (mRS . 2) for stroke patients. (B) All-cause mortality. (C)
Symptomatic intracranial haemorrhage. Adopted from references 28,36, and 40.

154

recanalization was achieved in 59.1% (Merci), 86.6% (Penumbra),


and 92.9% (stent retrievers). Functional independence (mRS 2)
was achieved in 31.5% (Merci), 36.6% (Penumbra), and 46.9%
(stent retrievers). The 3-month mortality rate was 37.8% in the
Merci studies, 20.7% in the Penumbra studies, and 12.3% in stent retriever studies. This study demonstrated improved outcomes after
CBT when performed with the latest generation of stent retrievers.
Major limitations of this and any other meta-analysis or comparison
between stroke trials are the heterogeneity of the stroke patients enrolled and the criteria for patient selection. This heterogeneity stems
from the multitude of causes of ischaemic stroke (e.g. atherosclerotic
occlusion, cardioembolism, spontaneous dissection, etc.) as well as
the variable sizes and locations of thrombi and occlusions. In addition,
the status of collaterals, the severity of the ischaemic penumbra, and
the size of the ischaemic core pre-treatment all have an effect on
prognosis and outcomes.
The interventional techniques and peri-procedural management
are highly variable. Patients undergoing catheter-based interventions
for acute ischaemic stroke receive either general anaesthesia (GA) or
conscious sedation. General anaesthesia may delay time to treatment, whereas conscious sedation may result in patient movement
and compromise the safety of the procedure. Analysis of 980 patients
who underwent intervention for acute anterior circulation stroke at
12 stroke centres between 2005 and 2009 found an overall recanalization rate of 68% and a symptomatic haemorrhage rate of 9.2%.
General anaesthesia was used in 44% of patients with no differences
in intracranial haemorrhage rates when compared with the conscious
sedation group. The use of GA was associated with poorer neurological outcome at 90 days (odds ratio 2.33; 95% CI 1.633.44;
P , 0.0001) and higher mortality (odds ratio 1.68; 95% CI 1.23
2.30; P , 0.0001) compared with conscious sedation. For example,
it is becoming increasingly more likely that the use of GA has a significant deleterious effect on outcomes and increased mortality.51
A recent study52 demonstrated that even stroke caused by the
acute occlusion of the internal carotid artery (with only 8 17% recanalization rate and 55% mortality rate when treated by thrombolysis)
can be effectively treated by CBT: successful revascularization of
extracranial internal carotid artery with acute stent implantation
was achieved in 95% of patients. The intracranial recanalization was
achieved in 61% of patients, who had simultaneous intracranial
artery occlusion. The mortality rate was 13.6% at 90 days and the favourable outcome (mRS 2) was 41%.
These data show that the latest generation of stent retrievers is
able to recanalize 8090% of occluded intracranial arteriesthree
times more compared with thrombolysis. However, it is not yet
known whether this translates to better clinical outcomes. The sufficient data on outcomes after primary CBT (without thrombolysis)
are still missing and trials comparing i.v. thrombolysis vs. primary
CBT are urgently needed and are being planned and initiated.

Adjuvant antithrombotic therapy


before/after reperfusion
One of the major differences between acute MI and acute stroke lies
in the intensity of adjuvant antithrombotic therapy connected to any
reperfusion strategy. Although antithrombotic therapy in acute MI is

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 15, 2014

Similar evidence from randomized trials is lacking in acute ischaemic stroke. A few years ago, CBT was performed with bulky devices,
and a significant risk of complications was present. In the last 35
years, several new clot retrieval devices (stent retrievers) have
been introduced and received CE mark for the use in European
patients. These devices (e.g. Solitairew or Trevow) are something
between a tiny self-expanding stent and a soft spider-web-like
basket for clot removal, and the risks of complications with this
latest generation stent retrievers are much smaller, whereas their
success rates are higher. Detailed information about CBT was published in the JACC white paper.44
The Penumbra Pivotal Stroke Trial45 included 125 patients, mostly
pre-treated by thrombolysis, with a mean NIHSS of 17.6, and demonstrated an 81.6% of recanalization rate. However, clinical outcomes
were not different (or were even worse) from previous thrombolytic
trials: 32.8% 90-day mortality, 75% unfavourable outcome (death or
disability), and 11.2% sICH.
The Solitaire With the Intention For Thrombectomy (SWIFT)
trial46 tested the Solitairew stent retriever against the Merci Retrieverw in patients within 8 h of stroke onset but was stopped early after
the randomization of 113 patients because an interim analysis
showed that the primary efficacy outcome (TIMI 2 or 3 flow) was
achieved more often with Solitairew (61 vs. 24%, OR 4.87, P ,
0.0001).46 Importantly, good neurological outcome (58 vs. 33%,
OR 2.78, P 0.0001) and 90-day mortality (17 vs. 38%, OR 0.34,
P 0.0001) were more favourable in the Solitairew group with a
markedly lower rate of sICH (2 vs. 11%, OR 0.14, P 0.057).
The TREVO 2 trial47 was similar to SWIFT and tested the Trevow
stent retriever vs. The Merci Retrieverw. Recanalization (TICI 2 or
greater) was higher with Trevow than with Merciw (86 vs. 60%,
OR 4.22, P , 0.0001) as was good clinical outcome (40 vs. 22%,
OR 2.39, P 0.013). There were no differences in the risk of sICH
(7 vs. 9%, OR 0.75, P 0.78) or 90-day mortality (33 vs. 24%, OR
1.61, P 0.18). An important finding from the SWIFT trial was that
the speed of recanalization with the stent retrievers was significantly
lower (36 min with Solitairew vs. 52 min with Merciw, P 0.038).
Several other devices with varying designs are currently being tested.
A recently published single-centre experience48 with 104 patients
treated with the Solitairew stent retrieval, 75% of them received also
thrombolysis. The recanalization rate was 78%. The mean NIHSS
decreased from 15.3 (before) to 7.8 (after treatment). Mortality
was 16% (anterior circulation) and 47.8% (posterior circulation).
Intracranial bleeding occurred in 8%.
Another recent multicentre retrospective review49 included 237
patients (mean age 64 years; mean baseline NIHSS 15) with acute
proximal intracranial anterior circulation occlusionendovascular
treatment was initiated .8 h (mean 15 h) from time last seen well.
The treatment selection was strictly based on MRI or CT perfusion
imaging. Successful revascularization was achieved in 74%. Parenchymal haematoma occurred in 9%. The 90-day mortality rate was 21.5%
and unfavourable outcome was in 55%.
The most recent meta-analysis50 of CBT registries identified 16 eligible published studies: 4 on the Merci device (n 357), 8 on the Penumbra system (n 455), and 4 on stent retrievers Solitairew or
Trevow (n 113). The mean procedural duration for Merci was
120 min. The mean puncture-to-recanalization time for Penumbra
was 64.6 min, and for stent retrievers, 54.7 min. Successful

P. Widimsky et al.

155

Reperfusion therapy of acute stroke

usually based on full-dose parenteral anticoagulation plus dual (or


sometimes even triple) antiplatelet therapy, such multidrug strategy
in acute stroke would be disastrous and cause many intracranial
bleedings. Antithrombotic therapy in acute stroke, especially when
treated by thrombolysis, should be cautious, low dose, usually with
a single agent. There are no trials at all assessing adjuvant antithrombotic therapies during/after direct catheter-based interventions in
acute stroke. This important topic is, however, beyond the scope
of this review.

Future: how to improve acute


stroke outcomes?

Summary
The evolution of reperfusion therapy in acute myocardial infarction
and acute ischaemic stroke has many similarities: thrombolysis is superior to placebo, i.a. thrombolysis is not superior to i.v., facilitated
intervention (thrombolysis followed by mechanical intervention) is
of questionable value, and direct mechanical recanalization without
thrombolysis clearly is (myocardial infarction) or possibly will be
(stroke) superior to thrombolysisbut only when started with no
or minimal delay (Table 2).
However, there are also substantial differences. Direct catheterbased thrombectomy in acute ischaemic stroke is more difficult
than primary angioplasty (in STEMI) in many ways: complex preintervention diagnostic workup, shorter time window for clinically effective reperfusion, need for an emergent multidisciplinary approach
from the first medical contact, vessel tortuosity, vessel fragility, no
evidence available about dosage and combination of peri-procedural
antithrombotic drugs, risk of intracranial bleeding, unclear respective
roles of thrombolysis and mechanical intervention, lower number of
suitable patients, and thus longer learning curves of the staff. Thus,
starting acute stroke interventional programme requires a lot of
learning, discipline, and humility.
Reperfusion strategies combining thrombolysis with immediate
intervention (i.a. thrombolysis or i.v. thrombolysis followed by

STEMI
death/
re-MI/
stroke

Acute stroke
death/severe
disability
(mRs > 2)

Conservative (no reperfusion)


I.V. thrombolysis

1530%
1116%

55 75%
48 63%

Local (i.a.) thrombolysis

1015%

51 60%

Facilitated intervention
(thrombolysis + intervention)

9 14%

59 79%

Primary catheter-based
intervention (no thrombolysis)

5 9%

No randomized
trials published

................................................................................

mechanical intervention) in general failed in both acute disorders


(STEMI and stroke) mainly due to the following reasons: (i) the fibrinolytic effect is always systemic and not directly dependent on
the dose or site of administration, (ii) the catheter manipulation in
a fibrinolytic state causes more bleeding complications than
simple i.v. thrombolysis, (iii) when thrombolysis is preceding mechanical intervention, the start of invasive procedure is always somewhat
delayed (this delay may be critical if the intervention is indicated for
clinical thrombolysis failure). Randomized trials comparing different
reperfusion strategies provided similar results in acute ischaemic
stroke as in STEMI. Thus, it might be expected that also a randomized
trial comparing direct (primary) CBT vs. i.v. thrombolysis could show
superiority of CBT if the mechanical intervention would be initiated
without delay. Such randomized trials are needed to define the role of
CBT in acute stroke treatment.

Funding
Preparation of this manuscript was supported by a research project of
Charles University Prague (PRVOUK P35).
Conflict of interest: none declared.

References
1. Chazov EI, Matveeva LS, Mazaev AV, Sargin KE, Sadovskaia GV, Ruda MI. Intracoronary administration of fibrinolysin in acute myocardial infarct. Ter Arkh 1976;48:8 19.
2. Gruppo Italiano per lo Studio della Streptochinasi nellInfarto Miocardico (GISSI).
Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction.
Lancet 1986;1:397 402.
3. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187
cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988;2:349360.
4. Meyer J, Merx W, Schweizer P, Dorr R, Lambertz H, Bethge C, Erbel R, Effert S.
Selective intracoronary lysis and transluminal coronary dilation as an immediate
measure in acute myocardial infarct. Verh Dtsch Ges Herz Kreislaufforsch 1982;48:
157 165.
5. Hartzler GO, Rutherford BD, McConahay DR, Johnson WL Jr, McCallister BD,
Gura GM Jr, Conn RC, Crockett JE. Percutaneous transluminal coronary angioplasty
with and without thrombolytic therapy for treatment of acute myocardial infarction.
Am Heart J 1983;106(5 Pt 1):965 973.
6. Zijlstra F, de Boer MJ, Hoorntje JC, Reiffers S, Reiber JH, Suryapranata H. A comparison of immediate coronary angioplasty with intravenous streptokinase in acute myocardial infarction. N Engl J Med 1993;328:680684.
7. Grines CL, Browne KF, Marco J, Rothbaum D, Stone GW, OKeefe J, Overlie P,
Donohue B, Chelliah N, Timmis GC. A comparison of immediate angioplasty with
thrombolytic therapy for acute myocardial infarction. The Primary Angioplasty in
Myocardial Infarction Study Group. N Engl J Med 1993;328:673 679.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 15, 2014

Facing the above-mentioned minimal benefits from i.v. thrombolysis


(vs. conservative treatment) in acute stroke and absence of any benefits from i.a. thrombolysis (vs. i.v. lysis alone), the future trials in acute
stroke must follow the way paved by acute myocardial infarction
trials: the future trials should compare i.v. thrombolysis alone vs.
catheter-based mechanical intervention alone (without lytics) for
the occlusion of major cerebral arteries. If such trials would demonstrate superiority of catheter-based thrombectomy, we can face in
future similar revolution in acute stroke treatment as we have been
facing in acute MI treatment in the past years.
Nevertheless, irrespective of the trial results, the most important
is to prevent acute strokesand this field is much more successful
already today. When the acute stroke occurs despite the preventive
measures, the critical value of every minute shortening the delay to
reperfusion therapy is essential. The continuous education should
be focused on boththe wide population knowledge of stroke
symptoms and the critical role of time and also to health care professionals, who must change their passive attitude to stroke treatment.

Table 2 Summary of the outcomes of various


reperfusion strategies in randomized trials

155a

24. Kennedy JW, Ritchie JL, Davis KB, Fritz JK. Western Washington randomized trial of
intracoronary streptokinase in acute myocardial infarction. N Engl J Med 1983;309:
1477 1482.
25. Rentrop KP, Feit F, Blanke H, Stecy P, Schneider R, Rey M, Horowitz S, Goldman M,
Karsch K, Meilman H. Effects of intracoronary streptokinase and intracoronary nitroglycerin infusion on coronary angiographic patterns and mortality in patients with
acute myocardial infarction. N Engl J Med 1984;311:1457 1463.
26. Simoons ML, Serruys PW, vd Brand M, Bar F, de Zwaan C, Res J, Verheugt FW,
Krauss XH, Remme WJ, Vermeer F. Improved survival after early thrombolysis in
acute myocardial infarction. A randomised trial by the Interuniversity Cardiology Institute in The Netherlands. Lancet 1985;2:578582.
27. Patel B, Kloner RA. Analysis of reported randomized trials of streptokinase therapy
for acute myocardial infarction in the 1980s. Am J Cardiol 1987;59:501504.
28. Widimsky P, Groch L, Zelzko M, Aschermann M, Bednar F, Suryapranata H. Multicentre randomized trial comparing transport to primary angioplasty vs immediate
thrombolysis vs combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory. The PRAGUE
study. Eur Heart J 2000;21:823 831.
29. Mazighi M, Meseguer E, Labreuche J, Amarenco P. Bridging therapy in acute ischemic
stroke. A systematic review and meta-analysis. Stroke 2012;43:1302 1308.
30. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A,
Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in acute
cerebral thromboembolism. JAMA 1999;282:2003 2011.
31. Ogawa A, Mori E, Minematsu K, Taki W, Takahashi A, Nemoto S, Miyamoto S,
Sasaki M, Inoue T, MELT Japan Study Group. Randomized trial of intraarterial infusion of urokinase within 6 hours of middle cerebral artery stroke: the middle cerebral
artery embolism local fibrinolytic intervention trial (MELT) Japan. Stroke 2007;38:
2633 2639.
32. Kharitonova T, Ahmed N, Thoren M, Wardlaw JM, von Kummer R, Glahn J,
Wahlgren N. Hyperdense middle cerebral artery sign on admission CT scanprognostic significance for ischaemic stroke patients treated with intravenous thrombolysis in the safe implementation of thrombolysis in Stroke International Stroke
Thrombolysis Register. Cerebrovasc Dis 2009;27:51 59.
33. De Silva DA, Brekenfeld C, Ebinger M, Christensen S, Barber PA, Butcher KS,
Levi CR, Parsons MW, Bladin CF, Donnan GA, Davis SM. The benefits of intravenous
thrombolysis relate to the site of baseline arterial occlusion in the Echoplanar
Imaging Thrombolytic Evaluation Trial (EPITHET). Stroke 2010;41:295 299.
34. Riedel CH, Zimmermann P, Jensen-Kondering U, Stingele R, Deuschl G, Jansen O.
The importance of size: successful recanalization by intravenous thrombolysis in
acute anterior stroke depends on thrombus length. Stroke 2011;42:1775 1777.
35. Saver JL, Yafeh B. Confirmation of tPA treatment effect by baseline severity-adjusted
end point reanalysis of the NINDS-tPA stroke trials. Stroke 2007;38:414 416.
36. Vermeer F, Oude Ophuis AJ, vd Berg EJ, Brunninkhuis LG, Werter CJ, Boehmer AG,
Lousberg AH, Dassen WR, Bar FW. Prospective randomised comparison between
thrombolysis, rescue PTCA, and primary PTCA in patients with extensive myocardial infarction admitted to a hospital without PTCA facilities: a safety and feasibility
study. Heart 1999;82:426 431.
37. Califf RM, Topol EJ, Stack RS, Ellis SG, George BS, Kereiakes DJ, Samaha JK, Worley SJ,
Anderson JL, Harrelson-Woodlief L. Evaluation of combination thrombolytic
therapy and timing of cardiac catheterization in acute myocardial infarction.
Results of thrombolysis and angioplasty in myocardial infarctionphase 5 randomized trial. TAMI Study Group. Circulation 1991;83:1543 1556.
38. ASS, ENT-4 Investigators. Primary versus tenecteplase-facilitated percutaneous coronary intervention in patients with ST-segment elevation acute myocardial infarction (ASSENT-4 PCI): randomised trial. Lancet 2006;367:569 578.
39. Armstrong PW, Gershlick AH, Goldstein P, Wilcox R, Danays T, Lambert Y,
Sulimov V, Rosell Ortiz F, Ostojic M, Welsh RC, Carvalho AC, Nanas J, Arntz HR,
Halvorsen S, Huber K, Grajek S, Fresco C, Bluhmki E, Regelin A, Vandenberghe K,
Bogaerts K, Van de Werf F; STREAM Investigative Team. Fibrinolysis or primary
PCI in ST-segment elevation myocardial infarction. N Engl J Med 2013;368:
1379 1387.
40. Broderick JP, Palesch YY, Demchuk AM, Yeatts SD, Khatri P, Hill MD, Jauch EC,
Jovin TG, Yan B, Silver FL, von Kummer R, Molina CA, Demaerschalk BM,
Budzik R, Clark WM, Zaidat OO, Malisch TW, Goyal M, Schonewille WJ,
Mazighi M, Engelter ST, Anderson C, Spilker J, Carrozzella J, Ryckborst KJ, Janis LS,
Martin RH, Foster LD, Tomsick TA; Interventional Management of Stroke (IMS) III
Investigators. Endovascular therapy after intravenous t-PA versus t-PA alone for
stroke. N Engl J Med. 2013;368:893 903.
41. Widimsky P, Budesnsky T, Vorac D, Groch L, Zelzko M, Aschermann M, Branny M,
Stasek J, Formanek P; PRAGUE Study Group Investigators. Long distance transport
for primary angioplasty vs immediate thrombolysis in acute myocardial infarction.
Final results of the randomized national multicentre trialPRAGUE-2. Eur Heart J
2003;24:94 104.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 15, 2014

8. Gibbons RJ, Holmes DR, Reeder GS, Bailey KR, Hopfenspirger MR, Gersh BJ.
Immediate angioplasty compared with the administration of a thrombolytic agent
followed by conservative treatment for myocardial infarction. The Mayo Coronary
Care Unit and Catheterization Laboratory Groups. N Engl J Med. 1993;328:
685 691.
9. Widimsky P, Janousek S, Vojacek J. Czech Society of Cardiology guidelines for the
diagnosis and treatment of acute myocardial infarction (Q-wave/ST elevations/
bundle branch block). Cor Vasa 2002;44:K123 K143.
10. Fletcher AP, Alkjaersig N, Lewis M, Tulevski V, Davies A, Brooks JE, Hardin WB,
Landau WM, Raichle ME. A pilot study of urokinase therapy in cerebral infarction.
Stroke 1976;7:135 142.
11. Mori E, Yoneda Y, Tabuchi M, Yoshida T, Ohkawa S, Ohsumi Y, Kitano K, Tsutsumi A,
Yamadori A. Intravenous recombinant tissue plasminogen activator in acute carotid
artery territory stroke. Neurology 1992;42:976 982.
12. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study
Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;
333:1581 1587.
13. Adams HP Jr, Adams RJ, Brott T, del Zoppo GJ, Furlan A, Goldstein LB, Grubb RL,
Higashida R, Kidwell C, Kwiatkowski TG, Marler JR, Hademenos GJ, Stroke
Council of the American Stroke Association. Guidelines for the early management
of patients with ischemic stroke: a scientific statement from the Stroke Council of the
American Stroke Association. Stroke 2003;34:1056 1083.
14. Bellon RJ, Putman CM, Budzik RF, Pergolizzi RS, Reinking GF, Norbash AM. Rheolytic
thrombectomy of the occluded internal carotid artery in the setting of acute ischemic stroke. Am J Neuroradiol 2001;22:526 530.
15. Jauch EC, Saver JL, Adams HP Jr, Bruno A, Connors JJ, Demaerschalk BM, Khatri P,
McMullan PW Jr, Qureshi AI, Rosenfield K, Scott PA, Summers DR, Wang DZ,
Wintermark M, Yonas H, American Heart Association Stroke Council, Council on
Cardiovascular Nursing, Council on Peripheral Vascular Disease, and Council on
Clinical Cardiology. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart
Association/American Stroke Association. Stroke 2013;44:870 947.
16. Adeoye O, Hornung R, Khatri P, Kleindorfer D. Recombinant tissue-type plasminogen activator use for ischemic stroke in the United States: a doubling of treatment
rates over the course of 5years. Stroke 2011;42:1952 1955.
17. Widimsky P, Wijns W, Fajadet J, de Belder M, Knot J, Aaberge L, Andrikopoulos G,
Baz JA, Betriu A, Claeys M, Danchin N, Djambazov S, Erne P, Hartikainen J, Huber K,
Kala P, Klinceva M, Kristensen SD, Ludman P, Ferre JM, Merkely B, Milicic D, Morais J,
Noc M, Opolski G, Ostojic M, Radovanovic D, De Servi S, Stenestrand U,
Studencan M, Tubaro M, Vasiljevic Z, Weidinger F, Witkowski A, Zeymer U, European Association for Percutaneous Cardiovascular Interventions. Reperfusion
therapy for ST elevation acute myocardial infarction in Europe: description of the
current situation in 30 countries. Eur Heart J 2010;31:943 957.
18. Kristensen SD, Fajadet J, Di Mario C, Kaifoszova Z, Laut KG, Deleanu D, Gilard M,
Guagliumi G, Goktekin O, Jorgova J, Kanakakis J, Ostojic M, Pereira H, Sabate M,
Sobhy M, Vrints C, Wijns W, Widimsky P. Implementation of primary angioplasty
in Europe: stent for life initiative progress report. EuroIntervention 2012;8:35 42.
19. Ahmed S, Antman EM, Murphy SA, Giugliano RP, Cannon CP, White H, Morrow DA,
Braunwald E. Poor outcomes after fibrinolytic therapy for ST-segment elevation
myocardial infarction: impact of age (a meta-analysis of a decade of trials).
J Thromb Thrombolysis 2006;21:119129.
20. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D, Larrue V, Lees KR,
Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D; ECASS
Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.
N Engl J Med 2008;359:1317 1329.
21. IST-3 Collaborative Group, Sandercock P, Wardlaw JM, Lindley RI, Dennis M,
Cohen G, Murray G, Innes K, Venables G, Czlonkowska A, Kobayashi A, Ricci S,
Murray V, Berge E, Slot KB, Hankey GJ, Correia M, Peeters A, Matz K, Lyrer P,
Gubitz G, Phillips SJ, Arauz A. The benefits and harms of intravenous thrombolysis
with recombinant tissue plasminogen activator within 6 h of acute ischaemic
stroke (the third international stroke trial [IST-3]): a randomised controlled trial.
Lancet 2012;379:2352 2363.
22. Wardlaw JM, Murray V, Berge E, Del Zoppo GJ. Thrombolysis for acute ischaemic
stroke. Cochrane Database Syst Rev 2009:CD000213. doi: 10.1002/
14651858.CD000213.pub2.
23. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC, Albers GW,
Kaste M, Marler JR, Hamilton SA, Tilley BC, Davis SM, Donnan GA, Hacke W;
ECASS ATLANTIS, NINDS and EPITHET rt-PA Study Group, Allen K, Mau J,
Meier D, del Zoppo G, De Silva DA, Butcher KS, Parsons MW, Barber PA, Levi C,
Bladin C, Byrnes G. Time to treatment with intravenous alteplase and outcome in
stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET
trials. Lancet 2010;375:1695 1703.

P. Widimsky et al.

Reperfusion therapy of acute stroke

42. Andersen HR, Nielsen TT, Rasmussen K, Thuesen L, Kelbaek H, Thayssen P,


Abildgaard U, Pedersen F, Madsen JK, Grande P, Villadsen AB, Krusell LR,
Haghfelt T, Lomholt P, Husted SE, Vigholt E, Kjaergard HK, Mortensen LS,
DANAMI-2 Investigators. A comparison of coronary angioplasty with fibrinolytic
therapy in acute myocardial infarction. N Engl J Med 2003;349:733 742.
43. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised
trials. Lancet 2003;361:1320.
44. White CJ, Abou-Chebl A, Cates CU, Levy EI, McMullan PW, Rocha-Singh K,
Weinberger JM, Wholey MH. Stroke intervention: catheter-based therapy for
acute ischemic stroke. J Am Coll Cardiol 2011;58:101116.
45. The Penumbra Pivotal Stroke Trial Investigators. The Penumbra Pivotal Stroke Trial:
safety and effectiveness of a new generation of mechanical devices for clot removal in
intracranial large vessel occlusive disease. Stroke 2009;40:2761 2768.
46. Saver JL, Jahan R, Levy EI, Jovin TG, Baxter B, Nogueira RG, Clark W, Budzik R,
Zaidat OO, SWIFT Trialists. Solitaire flow restoration device versus the Merci Retriever in patients with acute ischaemic stroke (SWIFT): a randomised,
parallel-group, non-inferiority trial. Lancet 2012;380:1241 1249.
47. Nogueira RG, Lutsep HL, Gupta R, Jovin TG, Albers GW, Walker GA,
Liebeskind DS, Smith WS; TREVO 2 Trialists. Trevo versus Merci retrievers for
thrombectomy revascularisation of large vessel occlusions in acute ischaemic
stroke (TREVO 2): a randomised trial. Lancet 2012;380:1231 1240.

155b
48. Dorn F, Stehle S, Lockau H, Zimmer C, Liebig T. Endovascular treatment of acute
intracerebral artery occlusions with the Solitaire stent: single-centre experience
with 108 recanalization procedures. Cerebrovasc Dis 2012;34:7077.
49. Jovin TG, Liebeskind DS, Gupta R, Rymer M, Rai A, Zaidat OO, Abou-Chebl A,
Baxter B, Levy EI, Barreto A, Nogueira RG. Imaging-based endovascular therapy
for acute ischemic stroke due to proximal intracranial anterior circulation occlusion
treated beyond 8 hours from time last seen well: retrospective multicenter analysis
of 237 consecutive patients. Stroke 2011;42:2206 2211.
50. Almekhlafi MA, Menon BK, Freiheit EA, Demchuk AM, Goyal M. A meta-analysis of
observational intra-arterial stroke therapy studies using the Merci device, Penumbra
system, and retrievable stents. AJNR Am J Neuroradiol 2012. Published online ahead of
print 26 July.
51. Abou-Chebl A, Lin R, Hussain MS, Jovin TG, Levy EI, Liebeskind DS, Yoo AJ, Hsu DP,
Rymer MM, Tayal AH, Zaidat OO, Natarajan SK, Nogueira RG, Nanda A, Tian M,
Hao Q, Kalia JS, Nguyen TN, Chen M, Gupta R. Conscious sedation versus
general anesthesia during endovascular therapy for acute anterior circulation
stroke: preliminary results from a retrospective, multicenter study. Stroke 2010;
41:1175 1179.
52. Papanagiotou P, Roth C, Walter S, Behnke S, Grunwald IQ, Viera J, Politi M, Korner H,
Kostopoulos P, Haass A, Fassbender K, Reith W. Carotid artery stenting in acute
stroke. J Am Coll Cardiol 2011;58:2363 2369.

Downloaded from http://eurheartj.oxfordjournals.org/ by guest on May 15, 2014

You might also like